Oxazolidines as 5-HT2A-antagonists

ABSTRACT

The invention relates to novel oxazolidine derivatives of the formula                    
     in which R 1 , R 2  and R 3  have the meanings stated in claim 1, their salts and processes for preparing the compounds according to the invention. 
     The compounds of the formula I act as 5-HT 2A  antagonists with a 5-HT reuptake-inhibiting, antidepressant or anxiolytic effect and can be used to produce pharmaceuticals.

This Application is a 371 of PCT/EP98/00637 filed Feb. 6, 1998.

The invention relates to compounds of the formula I

in which

R¹ is H, CN, Hal or OA,

R², R³ are each, independently of one another, H, CN, Hal or OA,

R² and R³ together are also methylenedioxy,

A is H, CF₃ or alkyl with 1-6 C atoms and

Hal is F, Cl, Br, I,

and the salts thereof.

5-[(2-Oxobenzimidazolin-1-yl)piperidinomethyl]-oxazolidin-2-ones witheffects on the central nervous system are disclosed, for example, in EP0 443 197. Indolepiperidines N-alkylated by indolalkyl radicals aredescribed, for example, in EP 0 683 16.3-Phenyl-5-[(4-R-X-piperidino)alkyl]oxazolidin-2-one derivatives inwhich R is phenyl and X is —O—, —S—, —SO— or —SO₂— and which haveeffects on the central nervous system are disclosed, for example, in EP0 635 505. Indolepiperidine derivatives with a tricyclic radical andeffects on the central nervous system are described, for example, in EP0 722 942. 4-Aryl-1-(indan-, dihydrobenzofuran- ordihydrobenzothiophenemethyl)-piperidine derivatives with an effect onserotoninergic and dopaminergic transmission and with an inhibitingeffect on 5-HT reuptake are described, for example, in WO 95/33721.

The invention was based on the object of finding novel compounds withvaluable properties, in particular those which can be used to producepharmaceuticals.

It has been found that, while being well tolerated, compounds of theformula I and their salts have particularly valuable pharmacologicalproperties because they display effects on the central nervous system,in particular dopamine-antagonistic and 5-HT reuptake-inhibiting effectssince they influence both serotoninergic and dopaminergic transmission.In particular, they have affinities for the 5-HT_(1A) and/or 5-HT_(2A)receptors.

The compounds of the formula I inhibit the binding of tritiatedserotonin receptor ligands to hippocampal receptors (Cossery et al.,European J. Pharmacol. 140 (1987), 143-155) and inhibit synaptosomalserotonin reuptake (Sherman et al., Life Sci. 23 (1978), 1863-1870). Inparticular, they bind to 5-HT_(2A) and D₂ receptors. In addition,changes in DOPA accumulation in the striatum and 5-HTP accumulation inthe raphe nuclei occur (Seyfried et al., European J. Pharmacol. 160(1989), 31-41). The 5-HT_(1A)-antagonistic effect is detected in vitrofor example by inhibition of the abolition caused by 8-OH-DPAT in theelectrically induced contraction of the guineapig ileum (Fozard andKilbinger, Br. J. Pharmacol. 86 (1985) 601P). The 5-HT_(1A)-antagonisticeffect is detected ex vivo by the inhibition of 5-HTP accumulationreduced by 8-OH-DPAT (Seyfried et al., European J. Pharmacol. 160(1989), 31-41).

Ex vivo inhibition of serotonin reuptake is detected by means ofsynaptosomal uptake inhibition (Wong et al., Neuropsychopharmacol. 8(1993), 23-33) and p-chloroamphetamine antagonism (Fuller et al., J.Pharmacol. Exp. Ther. 212 (1980), 115-119). The pharmacological testscan moreover be carried out in analogy to the methods described in WO95/33721.

The compounds of the formula I are therefore suitable both in veterinarymedicine and in human medicine for treating central nervous systemdysfunctions. They can be used for the prophylaxis and control of thesequelae of cerebral infarctions (apoplexia cerebri) such as stroke andcerebral ischaemias, and for the treatment of extrapyramidal motor sideeffects of neuroleptics, and of Parkinson's disease. However, they areparticularly suitable as pharmaceutical active substances foranxiolytics, anti-depressants, antipsychotics and/or for the treatmentof obsessive-compulsive disorder (OCD), anxiety states, panic attacks,depressions, psychoses, schizophrenia, delusional obsessions,Alzheimer's disease, migraine, anorexia, sleep disturbances, tardivedyskinesias, learning disorders, age-related memory impairments, eatingdisorders such as bulimia, substance abuse and/or sexual dysfunctions.

The compounds of the formula I and their physiologically acceptable acidaddition salts can therefore be used as pharmaceutical active substancesfor anxiolytics, antidepressants, antipsychotics, neuroleptics and/orantihypertensives, and for beneficially influencing obsessive-compulsivedisorder, eating disorders such as Bulimia, tardive dyskinesias,learning disorders and age-related memory impairments. They canfurthermore be employed as intermediates for preparing otherpharmaceutical active substances.

The invention thus relates to compounds of the formula I and to theirphysiologically acceptable acid addition salts.

The invention accordingly relates to the compounds of the formula I andto a process for preparing compounds of the formula I, characterized inthat

a) a compound of the formula II

in which R¹ has the meaning stated in Claim 1, and L is Cl, Br, I or afree or reactively functionally modified OH group,

 is reacted with a compound of the formula III

in which R² and R³ have the meanings given in Claim 1, or

b) a compound of the formula IV

in which R¹, R² and R³ have the meanings stated in Claim 1,

 is reacted with a compound of the formula V

in which L and L′ are each, independently of one another, Cl, Br, I or afree or reactively functionally modified OH group, or

c) a compound of the formula VI

in which R¹, R² and R³ have the meanings stated in Claim 1, ishydrogenated,

and/or in that a basic compound of the formula I is converted bytreatment with an acid into one of its salts.

Hereinbefore and hereinafter, the radicals R¹, R², R³ and L have themeanings stated for formulae I, II, III, IV and V unless expresslystated otherwise.

The invention likewise relates to pharmaceuticals of the formula I andtheir physiologically acceptable salts with 5-HT_(1A)- and5-HT_(2A)-antagonistic and 5-HT reuptake-inhibiting effects.

The invention relates to the compounds of the formula I according toClaim 1 and to the enantiomers thereof and the salts thereof.

It applies to all radicals which occur more than once, such as, forexample, A, that their meanings are independent of one another.

Alkyl has 1 to 10, preferably 1, 2, 3, 4, 5 or 6 C atoms. Alkyl istherefore in particular, for example, methyl, furthermore ethyl, propyl,isopropyl, butyl, isobutyl, sec-butyl or tert-butyl, also pentyl, 1-, 2-or 3-methylbutyl, 1,1-, 1,2- or 2,2-dimethylpropyl, 1-ethylpropyl,hexyl, 1-, 2-, 3- or 4-methylpentyl, 1,1-,; 1,2-, 1,3-, 2,2-, 2,3- or3,3-dimethylbutyl, 1- or 2-ethylbutyl, 1-ethyl-1-methylpropyl,1-ethyl-2-methylpropyl, 1,1,2- or 1,2,2-trimethylpropyl, alsofluoromethyl, difluoromethyl, trifluoromethyl, 1,1,1-trichloroethyl orpentafluoro-ethyl.

A—C— is hydroxyl or alkoxy, in particular, for example, methoxy, ethoxy,propoxy or butyloxy.

The compounds of the formula I, and the starting materials for preparingthem, are moreover prepared by methods known per se, as described in theliterature (for example in the standard works such as Houben-Weyl,Methoden der organischen Chemie [Methods of Organic Chemistry]Georg-Thieme-Verlag, Stuttgart), specifically under reaction conditionsknown and suitable for the reactions mentioned. It is moreover possibleto make use of variants which are known per se but which are notmentioned here in detail.

L in the compounds of the formula II, and L and L′ in the compounds ofthe formula V, are in each case independently of one another, Cl, Br, Ior a free or reactive esterified OH group.

If L is a reactive esterified OH group, this is preferablytrichloromethoxy, alkoxy such as, for example, methoxy, ethoxy, propoxyor butoxy, furthermore phenoxy, alkylsulfonyloxy with 1-6 C atoms(preferably methylsulfonyloxy) or arylsulfonyloxy with 6-10 C atoms(preferably phenyl- or p-tolylsulfonyloxy, also2-naphthalenesulfonyloxy). L in the compounds of the formula V inparticular is Cl, 1-imidazolyl, ethoxy, trichloromethoxy, phenoxy ornitrophenoxy.

The starting materials can, if required, also be formed in situ so thatthey are not isolated from the reaction mixture but are immediatelyreacted further to give the compounds of the formula I. It is possibleon the other hand to carry out the reaction stepwise.

The compounds of the formula I can preferably be obtained by reactingcompounds of the formula II with compounds of the formula III.

The starting materials of the formulae II and III are known in somecases. If they are not known, they can be prepared by methods known perse.

Primary alcohols of the formula II can be obtained, for example, byreducing the corresponding carboxylic acids or their esters. Treatmentwith thionyl chloride, hydrogen bromide, phosphorus tribromide orsimilar halogenated compounds affords the corresponding halides of theformula II.

3-(4-Piperidyl)indoles of the formula III can be prepared, for example,by reacting 4-piperidones with indole or corresponding R²- and/orR³-substituted derivatives with subsequent acid treatment andhydrogenation.

The reaction of compounds of the formula II with compounds of theformula III usually takes place in an inert solvent in the presence ofan acid-binding agent, preferably of an alkali metal or alkaline earthmetal hydroxide, carbonate or bicarbonate or of another salt of a weakacid of the alkali metals or alkaline earth metals, preferably ofpotassium, sodium, calcium or caesium. Addition of an organic base suchas triethylamine, dimethylaniline, pyridine or quinoline may also bebeneficial. The reaction time depends on the conditions used and isbetween a few minutes and 14 days, and the reaction temperature isbetween about 0° and 150°, normally between 20° and 130°.

Examples of suitable inert solvents are hydrocarbons such as hexane,petroleum ether, benzene, toluene or xylene; chlorinated hydrocarbonssuch as trichloroethylene, 1,2-dichloroethane, tetrachloromethane,chloroform or dichloromethane; alcohols such as methanol, ethanol,isopropanol, n-propanol, n-butanol or tert-butanol; ethers such asdiethyl ether, diisopropyl ether, tetrahydrofuran (THF) or dioxane;glycol ethers such as ethylene glycol monomethyl or monoethyl ether(methylglycol or ethylglycol), ethylene glycol dimethyl ether (diglyme);ketones such as acetone or butanone; amides such as acetamide,dimethylacetamide or dimethylformamide (DMF); nitriles such asacetonitrile; sulfoxides such as dimethyl sulfoxide (DMSO); carbondisulfite; carboxylic acids such as formic acid or acetic acid; nitrocompounds such as nitromethane or nitrobenzene; esters such as ethylacetate or mixtures of the solvents mentioned.

Compounds of the formula I can furthermore be obtained preferably byreacting compounds of the formula IV with compounds of the formula V.Suitable and preferred compounds of the formula V are dialkyl carbonatessuch as dimethyl, ditrichloromethyl or diethyl carbonate, chloroformicesters such as methyl or ethyl chloroformate, N,N′-carbonyldiimidazoleor phosgene.

Some of the starting materials of the formulae IV and V are known. Ifthey are unknown, they can be prepared by methods known per se. Thereaction takes place in solvents and at temperatures as described above.

Compounds of the formula VI can furthermore be converted by reductioninto compounds of the formula I. This is preferably carried out bycatalytic hydrogenation with, for example, palladium on active carbonand hydrogen.

Some of the starting materials of the formula VI are known. If they areunknown, they can be prepared by methods known per se. Reduction takesplace in solvents and at temperatures as described above.

It is furthermore possible to convert a compound of the formula I inwhich R¹ is OH by alkylation into an ether compound of the formula I inwhich R² is alkoxy.

A base of the formula I can be converted with an acid into the relevantacid addition salt, for example by reacting equivalent amounts of thebase and of the acid in an inert solvent such as ethanol andsubsequently evaporating. Particularly suitable acids for this reactionare those which afford physiologically acceptable salts. Thus, it ispossible to use inorganic acids, for example sulfuric acid, nitric acid,hydrohalic acids such as hydrochloric acid or hydrobromic acid,phosphoric acids such as ortho-phosphoric acid, sulfamic acid, alsoorganic acids, in particular aliphatic, alicyclic, araliphatic, aromaticor heterocyclic mono- or polybasic carboxylic, sulfonic or sulfuricacid, for example formic acid, acetic acid, propionic acid, pivalicacid, diethylacetic acid, malonic acid, succinic acid, pimelic acid,fumaric acid, maleic acid, lactic acid, tartaric acid, malic acid,citric acid, gluconic acid, ascorbic acid, nicotinic acid, isonicotinicacid, methane- or ethanesulfonic acid, ethanedisulfonic acid,2-hydroxyethanesulfonic acid, benzenesulfonic acid, p-toluenesulfonicacid, naphthalenemono- and disulfonic acids, lauryl sulfuric acid. Saltswith physiologically unacceptable acids, for example picrates, can beused to isolate and/or purify compounds of the formula I.

Compounds of the formula I according to the invention may, because oftheir molecular structure, be chiral and may accordingly occur in twoenantiomeric forms. They may therefore exist in racemic or in opticallyactive form.

Since the racemates and stereoisomers of the compounds according to theinvention may differ in pharmaceutical activity, it may be desirable touse the enantiomers. It is possible in these cases for the final productor else the intermediates to be fractionated into enantiomeric compoundsby chemical or physical procedures known to the skilled person, or to beemployed as such in the synthesis.

In the case of racemic amines, diastereomers are formed from the mixtureby reaction with an optically active resolving agent. Examples ofsuitable resolving agents are optically active acids such as the R and Sforms of tartaric acid, diacetyltartaric acid, dibenzoyltartaric acid,mandelic acid, malic acid, lactic acid, suitable N-protected amino acids(for example N-benzoylproline or N-benzenesulfonylproline) or thevarious optically active camphorsulfonic acids. It is also advantageousto separate the enantiomers by chromatography using an optically activeresolving agent (for example dinitrobenzoylphenylglycine, cellulosetriacetate or other derivatives of carbohydrates or chirally derivatizedmethacrylate polymers immobilized on silica gel). Suitable mobile phasesfor this purpose are aqueous or alcoholic solvent mixtures such as, forexample, hexane/isopropanol/acetonitrile, for example in the ratio82:15:3.

Salts with physiologically unacceptable acids, for example picrates, canbe used to isolate and/or purify compounds of the formula I.

The invention furthermore relates to the use of compounds of the formulaI and/or their physiologically acceptable salts for producingpharmaceutical compositions, in particular by non-chemical means. Forthis purpose they can be converted together with at least one solid orliquid and/or semiliquid excipient or ancillary substances and, whereappropriate, in combination with one or more other active substancesinto a suitable dosage form.

The invention furthermore relates to pharmaceutical compositionscomprising at least one compound of the formula I and/or one of itsphysiologically acceptable salts.

The compositions can be used as pharmaceuticals in human or veterinarymedicine. Suitable excipients are organic or inorganic substances whichare suitable for enteral (for example oral), parenteral or topicaladministration and do not react with the novel compounds, for examplewater, vegetable oils, benzyl alcohols, alkylene glycols, polyethyleneglycols, glycerol triacetate, gelatin, carbohydrates such as lactose orstarch, magnesium stearate, talc, petrolatum. Used for oraladministration are, in particular, tablets, pills, coated tablets,capsules, powders, granules, syrups, solutions or drops, for rectaladministration are suppositories, for parenteral administration aresolutions, preferably oily or aqueous solutions, also suspensions,emulsions or implants, for topical administration are ointments, creamsor dusting powders. The novel compounds can also be lyophilized and theresulting lyophilisates be used, for example, to produce products forinjection. The stated compositions can also be sterilized and/or containancillary substances such as lubricants, preservatives, stabilizersand/or wetting agents, emulsifiers, salts to influence the osmoticpressure, buffer substances, colorants, flavourings and/or several otheractive substances, for example one or more vitamins.

The compounds of the formula I according to the invention are, as arule, administered in analogy to other known products obtainablecommercially for the claimed indications (for example imipramine,fluoxetine, clomipramine), preferably in dosages between 0.1 mg and 500mg, in particular between 5 and 300 mg, per dosage unit. The daily doseis preferably between about 0.01 and 250 mg/kg, in particular between0.02 and 100 mg/kg, of body weight.

The specific dose for each patient depends, however, on a wide varietyof factors, for example on the activity of the specific compoundemployed, on the age, body weight, general state of health, sex, on thediet, on the time and route of administration, on the rate of excretion,combination of medicinal substances and severity of the particulardisorders for which the therapy applies. Oral administration ispreferred.

All temperatures are stated in °C. hereinbefore and hereinafter. In thefollowing examples, “usual workup” means: if necessary, water is added,the pH is adjusted if necessary, depending on the constitution of thefinal product, to values between 2 and 10, extraction is carried outwith ethyl acetate or dichloromethane, and the organic phase isseparated off, dried over sodium sulfate, evaporated and purified bychromatography on silica gel, there also being separation of the isomersdescribed below, and/or by crystallization. Rf values on silica gel;mobile phase: ethyl acetate/methanol 9:1.

Mass spectrometry:

EI (electron impact ionization): M⁺

FAB (fast atom bombardment): (M+H)⁺

EXAMPLE 1

A solution of5-(methanesulfonyloxymethyl)-3-p-methoxyphenyloxazolidin-2-one[obtainable by reacting 2,3-epoxypropanol with N-benzyl-p-methoxyanilineto give 1-(N-benzyl-p-methoxyanilinopropane-2,3-diol, hydrogenolysis togive 1-p-methoxyanilinopropane-2,3-diol, reacting with diethyl carbonateto give 5-hydroxymethyl-3-p-methoxyphenyloxazolidin-2-one and reactionwith CH₃SO₂Cl] in acetonitrile is mixed with equimolar amounts of4-(3-indolyl)piperidine (“A”), potassium iodide and potassium carbonate,heated under reflux for 16 hours and then subjected to the usual workup.This results in3-(4-methoxyphenyl)-5-[4-(3-indolyl)-1-piperidinylmethyl]oxazolidin-2-one,m.p. 151-153°.

Analogous reaction of “A”

with(5S)-5-(methanesulfonyloxymethyl)-3-p-methoxy-phenyloxazolidin-2-oneresults in

(5S)-(−)3-(4-methoxyphenyl)-5-[4-(3-indolyl)-1-piperidinylmethyl]oxazolidin-2-one,hydrochloride, m.p. 234-236°, α_(D) ²⁰−56° (c=1, methanol);

with (5S)-5-(methanesulfonyloxymethyl)-3-p-chloro-phenyloxazolidin-2-oneresults in

(5S)-(−)3-(4-chlorophenyl)-5-[4-(3-indolyl)-1-piperidinylmethyl]oxazolidin-2-one,m.p. 188-189°, α_(D) ²⁰−28° (c=1, DMSO); hydrochloride, m.p. 260-263°;

with 5-(methanesulfonyloxymethyl)-3-p-cyanophenyl-oxazolidin-2-oneresults in

3-(4-cyanophenyl)-5-[4-(3-indolyl)-1-piperidinyl-methyl]oxazolidin-2-one.

with 5-(methanesulfonyloxymethyl)-3-phenyloxazolidin-2-one results in

3-phenyl-5-[4-(3-indolyl)-1-piperidinylmethyl]-oxazlidin-2-one;

with 5-(methanesulfonyloxymethyl)-3-p-fluorophenyl-oxazolidin-2-oneresults in

3-(4-fluorophenyl-5-[4-(3-indolyl)-1-piperidinylmethyl]oxazolidin-2-one.

Analogous reaction of 4-(5H-1,3-dioxolo[4,5-f]-indol-7-yl)piperidine(“B”)

with(5S)-5-(methanesulfonyloxymethyl)-3-p-methoxy-phenyloxazolidin-2-oneresults in

(5S)-(−)3-(4-methoxyphenyl)-5-[4-(5H-1,3-dioxolo[4,5-f]indol-7-yl)-1-piperidinylmethyl]-oxazolidin-2-one, hydrochloride,m.p. 232-234°, α_(D) ²⁰−50.5° (c=1, methanol);

with (5S)-5-(methanesulfonyloxymethyl)-3-p-chlorophenyloxazolidin-2-oneresults in

(5S)-(−)3-(4-chlorophenyl)-5-[4-(5H-1,3-dioxolo[4,5-f]indol-7-yl)-1-piperidinylmethyl]-oxazolidin-2-one.

Analogous reaction of 4-(5-fluoro-3-indolyl)-piperidine (“C”)

with(5S)-5-(methanesulfonyloxymethyl)-3-p-methoxy-phenyloxazolidin-2-oneresults in

(5S)-(−)3-(4-methoxyphenyl)-5-[4-(5-fluoro-3-indolyl)-1-piperidinylmethyl]oxazolidin-2-one,hydrochloride, m.p. 233-234°, α_(D) ²⁰−58.5° (c=1, DMSO);

with 5-(methanesulfonyloxymethyl)-3-p-cyanophenyl-oxazolidin-2-oneresults in

3-(4-cyanophenyl)-5-[4-(5-fluoro-3-indolyl)-1-piperidinylmethyl]oxazolidin-2-one,hydrochloride, m.p. 290-292°;

with (5S)-5-(methanesulfonyloxymethyl)-3-p-cyanophenyl-oxazolidin-2-oneresults in

(5S)-(−)3-(4-cyanophenyl)-5-[4-(5-fluoro-3-indolyl)-1-piperidinylmethyl]oxazolidin-2-one,hydrochloride, m.p. 203-204°; α_(D) ²⁰−36.5° (c=1, DMSO);

with (5R)-5-(methanesulfonyloxymethyl)-3-p-cyanophenyl-oxazolidin-2-oneresults in

(5R)-(+)3-(4-cyanophenyl)-5-[4-(5-fluoro-3-indolyl)-1-piperidinylmethyl]oxazolidin-2-one,hydrochloride, m.p. 286-287°; α_(D) ²⁰+41.5° (c=1, DMSO).

Analogous reaction of 4-(5-cyano-3-indolyl)-piperidine (“D”)

with 5-(methanesulfonyloxymethyl)-3-p-cyanophenyl-oxazolidin-2-oneresults in

3-(4-cyanophenyl)-5-[4-(5-cyano-3-indolyl)-1-piperidinylmethyl]oxazolidin-2-one,hydrochloride, m.p. 290°;

with (5S)-5-(methanesulfonyloxymethyl)-3-p-fluoro-phenyloxazolidin-2-oneresults in

(5S)-(−)-3-(4-fluorophenyl)-5-[4-(5-cyano-3-indolyl)-1-piperidinylmethyl]oxazolidin-2-one,hydrochloride, m.p. 252-253°;

with (5S)-5-(methanesulfonyloxymethyl)-3-p-cyano-phenyloxazolidin-2-oneresults in

(5S)-(−)-3-(4-cyanophenyl)-5-[4-(5-cyano-3indolyl)-1-piperidinylmethyl]oxazolidin-2-one,hydrochloride, m.p. 270-271°, α_(D) ²⁰−38.7° (c=1, DMSO);

with (5R)-5-(methanesulfonyloxymethyl)-3-p-cyano-phenyloxazolidin-2-oneresults in

(5R)-(+)-3-(4-cyanophenyl)-5-[4-(5-cyano-3-indolyl)-1-piperidinylmethyl]oxazolidin-2-one,hydrochloride, m.p. 270-272°, α_(D) ²⁰+37.7° (c=1, DMSO);

with 5-(methanesulfonyloxymethyl)-3-p-fluorophenyl-oxazolidin-2-oneresults in

3-(4-fluorophenyl)-5-[4-(5-cyano-3-indolyl)-1-piperidinylmethyl]oxazolidin-2-one,hydrochloride, m.p. 264-268°;

with 5-(methanesulfonyloxymethyl)-3-phenyloxazolidin-2-one results in

3-phenyl-5-[4-(5-cyano-3-indolyl)-1-piperidinylmethyl]-oxazolidin-2-one,hydrochloride hydrate, m.p. 183-185°;

with (5R)-5-(methanesulfonyloxymethyl)-3-p-fluoro-phenyloxazolidin-2-oneresults in

(5R)-(+)-3-(4-fluorophenyl)-5-[4-(5-cyano-3-indolyl)-1-piperidinylmethyl]oxazolidin-2-one,hydrochloride, m.p. 184-188°, α_(D) ²⁰+27.2° (c=1, DMSO).

Analogous reaction of 4-(6-fluoro-3-indolyl)-piperidine (“E”)

with (5S)-5-(methanesulfonyloxymethyl)-3-p-cyanophenyl-oxazolidin-2-oneresults in

(5S)-(−)-3-(4-cyanophenyl)-5-[4-(6-fluoro-3-indolyl)-1-piperidinylmethyl]oxazolidin-2-one,hydrochloride, m.p. 287-288°, α_(D) ²⁰−38.4° (c=1, DMSO);

with 5-(methanesulfonyloxymethyl)-3-p-fluorophenyl-oxazolidin-2-oneresults in

3-(4-fluorophenyl)-5-[4-(6-fluoro-3-indolyl)-1-piperidinylmethyl]oxazolidin-2-one,hydrochloride, m.p. 257-259°;

with (5R)-5-(methanesulfonyloxymethyl)-3-p-cyanophenyl-oxazolidin-2-oneresults in

(5R)-(+)-3-(4-cyanophenyl)-5-[4-(6-fluoro-3-indolyl)-1-piperidinylmethyl]oxazolidin-2-one,hydrochloride, m.p. 288-290°, α_(D) ²⁰+38.8° (c=1, DMSO);

with 5-(methanesulfonyloxymethyl)-3-phenyloxazolidin-2-one results in

3-phenyl-5-[4-(6-fluoro-3-indolyl)-1-piperidinyl-methyl]oxazolidin-2-one,hydrochloride, m.p. 234-236°.

EXAMPLE 2

A solution of1-[4-(3-indolyl)-1-piperidinyl]-3-(4-methoxyanilino)-2-propanol indichloromethane is mixed with equimolar amounts of ditrichloromethylcarbonate and stirred for 5 hours. The usual workup results in3-(4-methoxyphenyl)-5-[4-(3-indolyl)-1-piperidinylmethyl]oxazolidin-2-one,m.p. 151-153°.

EXAMPLE 3

Hydrogen is passed for 1 hour through a solution of5-[4-(3-indolyl)-3,6-dihydro-2H-pyridin-1-ylmethyl]-3-(4-methoxyphenyl)oxazolidin-2-one[obtainable by dehydration of3-(4-methoxyphenyl)-5-[4-(3-indolyl)-4-hydroxy-1-piperidinylmethyl]oxazolidin-2-onewhich was prepared by reacting3-(4-methoxyphenyl)-5-[4-oxo-1-piperidinylmethyl]oxazolidin-2-one withindole] in methanol in the presence of palladium (10% on active carbon).Removal of the catalyst and the usual workup results in3-(4-methoxyphenyl)-5-[4-(3-indolyl)-1piperidinylmethyl]oxazolidin-2-one,m.p. 151-153°.

The following examples relate to pharmaceutical compositions:

Example A

Vials

A solution of 100 g of an active substance of the formula I and 5 g ofdisodium hydrogen phosphate in 3 l of double-distilled water is adjustedto pH 6.5 with 2 N hydrochloric acid, sterilized by filtration,dispensed into vials, lyophilized under sterile conditions and sealedsterile. Each vial contains 5 mg of active substance.

Example B

Suppositories

A mixture of 20 g of an active substance of the formula I with 100 g ofsoya lecithin and 1400 g of cocoa butter is melted, poured into mouldsand left to cool. Each suppository contains 20 mg of active substance.

Example C

Solution

A solution is prepared from 1 g of an active substance of the formula I,9.38 g of NaH₂PO₄2H₂O, 28.48 g of Na₂HPO₄12H₂O and 0.1 g of benzalkoniumchloride in 940 ml of double-distilled water. The pH is adjusted to 6.8,and the solution is made up to 1 l and sterilized by irradiation.

Example D

Ointment

500 mg of an active substance of the formula I are mixed with 99.5 g ofpetrolatum under aseptic conditions.

Example E

Tablets

A mixture of 1 kg of active substance of the formula I, 4 kg of lactose,1.2 kg of potato starch, 0.2 kg of talc and 0.1 kg of magnesium stearateis compressed to tablets in a conventional way so that each tabletcontains 10 mg of active substance.

Example F

Coated Tablets

Tablets are made in analogy to Example E and are then provided in aconventional way with a coating of sucrose, potato starch, talc,tragacanth and dye.

Example G

Capsules

2 kg of active substance of the formula I are packed in a conventionalway into hard gelatine capsules so that each capsule contains 20 mg ofthe active substance.

Example H

Ampoules

A solution of 1 kg of active substance of the formula I in 60 ofdouble-distilled water is sterilized by filtration, dispensed intoampoules, lyophilized under sterile conditions and sealed sterile. Eachampoule contains 10 mg of active substance.

What is claimed is:
 1. A compound of the formula I

in which R¹ is H, CN, Hal or OA, R², R³ are each, independently of oneanother, H, CN, Hal or OA, or R² and R³ together are methylenedioxy, Ais H, CF₃ or alkyl, optionally substituted, with 1-6 C atoms and Hal isF, Cl, Br, I, or a salt thereof.
 2. An enantiomer of the compound of theformula I according to claim
 1. 3. A compound of the formula I accordingto claim 1 which is a)(5S)-(−)-3-(4-chlorophenyl)-5-[4-(3-indolyl)-1-piperidinylmethyl]oxazolidin-2-one;b)3-(4-cyanophenyl)-5-[4-(5-cyano-3-indolyl)-1-piperidinylmethyl]oxazolidin-2-one;c)(5S)-(−)-3-(4-cyanophenyl)-5-[4-(6-fluoro-3-indolyl)-1-piperidinylmethyl]oxazolidin-2-one;d)(5R)-(+)-3-(4-cyanophenyl)-5-[4-(5-fluoro-3-indolyl)-1-piperidinylmethyl]oxazolidin-2-one;e)(5R)-(+)-3-(4-cyanophenyl)-5-[4-(6-fluoro-3-indolyl)-1-piperidinylmethyl]oxazolidin-2-one;f)3-phenyl-5-[4-(5-cyano-3-indolyl)-1-piperidinylmethyl]oxazolidin-2-one;g)3-phenyl-5-[4-(6-fluoro-3-indolyl)-1-piperidinylmethyl]oxazolidin-2-one;or a salt thereof.
 4. A process for the preparation of a compound offormula I according to claim 1, which comprises: a) reacting a compoundof the formula II

in which R¹ has the meaning stated in claim 1, and L is Cl, Br, I or afree or reactively functionally modified OH group,  with a compound ofthe formula III

in which R² and R³ have the meanings given in claim 1, and optionallyconverting a basic compound of the formula I by treatment with an acidinto a salt thereof.
 5. A process for the production of a pharmaceuticalcomposition, comprising combining together a compound of the formula Iaccording to claim 1 and/or one of its physiologically tolerated saltsor one of its enantiomers with at least one solid, liquid or semiliquidexcipient or ancillary substance and, where appropriate, in combinationwith one or more other active substances, into a suitable dosage form.6. A pharmaceutical composition comprising at least one compound ofclaim 1 or at least one of its physiologically acceptable salts, and apharmaceutically acceptable carrier.
 7. A method comprisingadministering a compound to an animal of the formula I according toclaim 1 or a physiologically acceptable salt thereof for controlling asequela of stroke or a cerebral ischaemia, or for treating anobsessive-compulsive disorder (OCD), an anxiety state, a panic attack,depression, psychosis, schizophrenia or Parkinson's disease.
 8. Acompound of the formula I according to claim 1 or a physiologicallyacceptable salt thereof which exhibits a 5-HT_(2A) antagonist with 5-HTreuptake-inhibiting effect wherein Hal is F or Cl.
 9. A method ofproducing a pharmaceutical composition comprising combining a compoundaccording to claim 1 or a physiologically acceptable salt thereof with apharmaceutically acceptable carrier.
 10. A pharmaceutical preparationcomprising a compound according to claim 1 and a physiologicallyacceptable carrier.
 11. A compound of the formula I

wherein R¹ is H, CN, Hal or OA; R², R³ are each, independently of oneanother, H, CN, Hal, or OA; or R² and R³ together are methylenedioxy; Ais methy, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, pentyl,1-, 2- or 3-methylbutyl, 1,1-, 1,2- or 2,2-dimethylpropyl,1-ethylpropyl, hexyl, 1-, 2-, 3-, or 4-methylpentyl, 1,1-, 1,2-, 1,3-,2,2-, 2,3- or 3,3-dimethylbutyl, 1- or 2-ethylbutyl,1-ethyl-1-methylpropyl, 1-ethyl-2-methylpropyl, 1,1,2- or1,2,2-trimethylpropyl, fluoromethyl, difluoromethyl, trifluoromethyl,1,1,1-trichloroethyl or pentafluoroethyl; and Hal is F, Cl, Br, or I; ora salt thereof.
 12. A compound of formula I according to claim 1 whereinat least one of R¹, R² or R³ is OA which is hydroxyl or alkoxy.
 13. Aprocess according to claim 5 wherein the ancillary substance is alubricant, a preservative, a stabilizer, a wetting agent, emulsifier,salt to influence the osmotic pressure, buffer substance, colorant,flavouring and/or vitamin.